Gold-Catalyzed Dearomative Spirocyclization of N-Aryl Alkynamides for the Synthesis of Spirolactams

Article abstract of DOI:10.1021/acs.joc.7b03125

A catalytic redox-neutral method for the synthesis of spirolactams proceeding through the dearomative spirocyclization of N-aryl alkynamides is reported. In contrast to stoichiometric activating agents employed for related transformations, we show that the use of 5 mol % of Au(PPh₃)Cl and AgOTf in dichloroethane at 50-80 °C leads to selective spirocyclization, furnishing the products in yields of 35-87%. The substrate scope of the reaction is good, with both electron-donating and electron-withdrawing groups being tolerated around the arene ring, as well as substitution at the amide nitrogen. The identity of the para-alkoxy group on the arene ring is key to achieving selectivity for spirocyclization over alternative mechanistic pathways. While the presence of a para-methoxy group leads to trace amounts of the desired spirolactams, the para-tert-butoxy or para-hydroxy substrate analogues furnish the spirolactams in good yield with high selectivity.

Full text of DOI:10.1021/acs.joc.7b03125

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Article
Gold-Catalyzed Dearomative Spirocyclization of N-
Aryl Alkynamides for the Synthesis of Spirolactams
Taylor L. Vacala, Paul R. Carlson, Asa Arreola-Hester,
Chloe G. Williams, Evana W. Makhoul, and Paul A. Vadola
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03125 • Publication Date (Web): 08 Jan 2018
Downloaded from http://pubs.acs.org on January 8, 2018
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Page 1 of 35
The Journal of Organic Chemistry
Gold-Catalyzed Dearomative Spirocyclization of N-Aryl Alkynamides
1
2
3
for the Synthesis of Spirolactams
Taylor L. Vacala, Paul R. Carlson, Asa Arreola-Hester, Chloé G. Williams, Evana W. Makhoul, and Paul A.
Vadola*
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
5
5
5
5
5
5
5
5
5
5
6
Department of Chemistry, DePaul University, 1110 West Belden Avenue, Chicago, Illinois, 60614
Me
O
t
Me
R = Bu
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Au(PPh
3
)Cl & AgOTf 5 mol %
8
7% yield
RO
DCE, 80 °C
HN
spirolactam
R = Me
0% yield
N
H
O
O
O
O
Me
identity of R is key
to spirocyclization
O
Me
N
O
Ph
F
3
C
Me
HN
NH
7
8%
O
O
65%
85%
CyHN
O
ABSTRACT: A catalytic redox-neutral method for the synthesis of spirolactams proceeding through the
dearomative spirocyclization of N-aryl alkynamides is reported. As opposed to stoichiometric activating agents
3
employed for related transformation we show that the use of 5 mol % of Au(PPh )Cl and AgOTf in
dichloroethane at 50-80 °C leads to selective spirocyclization, furnishing the products in yields of 35-87%. The
substrate scope of the reaction is good, with both electron-donating and withdrawing groups being tolerated
around the arene ring, as well as substitution at the amide nitrogen. The identity of the para-alkoxy group on the
arene ring is key to achieving selectivity for spirocyclization over alternative mechanistic pathways. While the
presence of a para-methoxy group leads to trace amounts of the desired spirolactams, the para-tert-butoxy or
para-hydroxy substrate analogs furnish the spirolactams in good yield with high selectivity.
Introduction:
The dearomative spirocyclization of substituted phenols and related alkoxyarenes, as a mechanistic paradigm,
1
,2,3,4
has inspired the development of a variety of methods for the construction of spirocyclic compounds.
Spirocycles have long attracted the attention of organic chemists given the prevalence of spirocyclic scaffolds
within natural products. Increasing interest in these compounds can also be seen in the field of medicinal
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chemistry given the high degree of three-dimensionality and conformational rigidity spirocyclic motifs impart
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
to compounds.
Of the various classes of compounds capable of undergoing dearomative spirocyclization (1 → 2, Figure 1),
2
alkynyl arenes have become popular precursors to an array of functionalized spirocycles. The majority of these
methods rely on electrophilic activation of the pendant alkyne by stoichiometric Brønsted acids or halogen
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
electrophiles to induce nucleophilic attack of the arene. In addition, a number of oxidative methods have also
4
been reported. Our group, however, has been interested in the development of redox-neutral catalytic processes
6
(
3 → 6, Figure 1). The use of mild Lewis acid catalysts for alkyne activation, in place of more traditional
alkynophilic reagents, can offer improved atom economy and increased functional group tolerance, thereby
granting access to more complex spirocyclic products.
R'
O
R'
alkynophilic electrophile (E)
RO
E
dearomative
ipso-cyclization
X
X
O
O
1
2
alkynyl arene
spirocycle
O
Me
X
Me
MeO
AuLn
X
6
alkynyl
arene
O
spirocycle O
8
fused bicycle
Me
O
MeO
[Au]
Me
Me
O
MeO
[Au]
[
Au]
X
O ortho-
cyclization
X
3
5
X
O
ipso-
cyclization
7
O
Me
O
Me
demethylation
i. 1,2-alkyl shift
ii. deprotonation
[
Au]
4
X
Figure 1. Divergent cyclization pathways of alkynyl arenes
We previously developed an efficient method for the synthesis of spirolactones (11, Figure 2) from aryl
6
alkynoate esters (9) employing a gold-centered catalyst. Recently, we have begun exploring the reactivity of
the analogous N-aryl alkynamides (10, Figure 2), in an attempt to extend our ipso-cyclization method to the
synthesis of spirolactams (6, X = NH, Figure 1). Ipso-cyclization protocols for amide-linked alkynyl arenes
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The Journal of Organic Chemistry
3
g
have been developed, including methods proceeding through the action of stoichiometric quantities of acids,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
c-f
4
electrophilic halogenating agents, or oxidants for the in situ generation of radical activators. However, there
have been few reports concerned with redox-neutral catalytic transformation, and those which have been
7
reported include the ipso-cyclization event as part of larger cascade processes.
O
Me
3
Au(PPh )Cl 5 mol %
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Me
AgOTf 5 mol %
DCE, rt
1 equiv water
O
MeO
11
O
X = O
91% yield
spirolactone
X
O
9
X = O
10 X = NH
Me
alkynyl arene
MeO
Au(PPh
3
)Cl 5 mol %
O
AgOTf 5 mol %
DCE, rt
N
O
1
2
H
1
equiv water
8
1% yield
β-ketoamide
X = NH
Figure 2. Differing reactivity of alkynyl aryl esters and amides
Here we present our efforts towards the development of a general approach to the synthesis of spirolactams
(
6, X = NH, Figure 1) from readily accessible N-aryl alkynamides (1, X = NH, Figure 1). While our previously
reported ester ipso-cyclization conditions failed to deliver the desired spirolactams, even at elevated
temperatures, we found that the identity of the arene’s para-substituent was key to achieving selectivity for the
ipso-cyclization of these substrates.
Results and Discussion:
We began our study of N-aryl alkynamide ipso-cyclization by subjecting amide 10 to our aryl alkynoate ester
3
ipso-cyclization conditions: 5 mol % of the catalyst precursor Au(PPh )Cl and the silver salt activator AgOTf in
dichloroethane (DCE, c = 0.1 M) with one equivalent of water at room temperature (Figure 2). We were
surprised to find that the major product of the reaction was the β-ketoamide 12, which was formed in 81% yield
1
after 24 h, with a trace amount of the target spirolactam 13 observed by crude H NMR analysis (entry 1, Table
1
). Increasing the reaction temperature to 50 °C failed to yield any improvement (entry 2).
Given the high reaction rate we regularly observed for ester ipso-cyclization, with most reactions complete in
3
under an hour, it appeared that the amide substrates were less reactive towards our Au(PPh )Cl/AgOTf catalyst
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system. Similar rate differences for these two substrate classes were also observed in previous studies aimed at
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
8
ortho-cyclization reactions (3 → 8, Figure 1). Although the presence of water in the reaction mixture was
clearly a problem, the likely outcome of removing water from the reaction mixture was unclear as water proved
critical to the selectivity of ipso-cyclization over ortho-cyclization for the ester substrates. A dramatic decrease
in overall percent conversion of amide 10 was observed in the absence of water with β-ketoamide 12 still
formed as the major product (entries 3 & 4, Table 1).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Table 1. Attempted Ipso-Cyclization With and Without Water
Me
Me
O
Me
MeO
MeO
Au(PPh
3
)Cl 5 mol %
O
AgOTf 5 mol %
DCE [0.1M]
water X equiv
HN
N
H
O
N
H
O
10
13
12
13 12 (10)
O
entry
water
T (ºC) % yield:
b
1
2
3
4
1 equivalent
23
50
50
80
4
3
81
78
(6)
(5)
1 equivalent
---
---
>1 35 (58)
>1 28 (60)
a
b1
All reactions were analyzed after 24 h. H NMR yields determined using dibenzyl ether as an internal
standard.
At this stage, it became clear that that the arene ring was simply not reactive enough to engage the activated
alkyne in an ipso-cyclization. We revisited our proposed reaction mechanism (Figure 1) and considered ways in
which we could modify the reaction to enhance the likelihood of the ipso-cyclization event (3 → 4) and,
furthermore, drive the initial spirocyclic oxocarbenium intermediate to undergo loss of the alkyl group from the
para-alkoxy substituent (14 → 15, Figure 3).
O
O
Me
O
Me
R
R
[
Au] heterolytic C–O
[Au]
stable
more labile
than methyl
HN
bond cleavage
HN
15
carbocation
1
4
O
Me
O
Me
Me
Me
O
Au(PPh )Cl 5 mol %
3
87% yield
4% β-ketoamide)
(
Me
AgOTf 5 mol %
DCE, 80 ºC
HN
N
H
O
1
6
13
O
Figure 3. Modifying the para-substituent to promote ipso-cyclization over alkyne hydration
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We speculated that if the substrate was indeed undergoing the necessary ipso-cyclization step to reach
intermediate 14, conversion to intermediate 15 might be possible if the methoxy group of the lead substrate 10
was exchanged for a para-alkoxy group capable of undergoing heterolytic C–O bond cleavage once in the
oxocarbenium state (14 → 15). This process would liberate a stable carbocationic species, which could provide
a driving force for the overall transformation. The moderate stability of the tert-butyl cation led us to synthesize
substrate 16, bearing a para-tert-butoxy group.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
We subjected 16 to 5 mol % of Au(PPh
3
)Cl and AgOTf in DCE at 50 °C. Analysis of the reaction mixture by
H NMR revealed that the spirolactam 13 was formed in 71% yield after 24 h, along with 16% β-ketoamide 17;
% of unreacted starting material was also observed. Increasing the reaction temperature to 80 °C further
1
9
improved the reaction, yielding the spirolactam in 87% yield, with no starting material remaining and only 4%
of β-ketoamide observed. Thus, we were able to achieve the selective ipso-cyclization of an N-aryl alkynamide
substrate to the corresponding spirolactam under catalytic conditions in bench-top solvent, by judicious
selection of the para-alkoxy group.
a
Table 2. Optimization of Ipso-Cyclization Conditions
Me
O
Me
Me
tBuO
tBuO
catalyst (5 mol %)
O
DCE, T
HN
N
H
O
N
H
O
1
6
13
O
17
entry catalyst
activator
T (ºC) % yield:
b
13 17 (16)
1
Au(PPh
Au(PPh
3
)Cl
)Cl
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
23
50
50
80
80
80
80
80
23
50
80
50
80
80
50
80
16 35 (30)
71 16 (9)
54 11 (10)
2
3
3c
3
Au(PPh )Cl
4
Au(PPh
3
)Cl
87
4
5
(0)
5c
Au(PPh )Cl
62
(12)
3
6
7
8
9
Au(PPh
Au(PPh
Au(PPh
3
3
3
)Cl
)Cl
)Cl
AgSbF
6
45 15 (28)
35
(48)
AgBF
AgNTf
---
4
9
2
12 15 (56)
10 42 (33)
34 30 (13)
Au(XPhos)SbF
Au(XPhos)SbF
Au(XPhos)SbF
6
•MeCN
•MeCN
•MeCN
1
0
6
---
11
6
---
70
3
9
(0)
12d Au(PPh
)Cl
AgOTf
---
3
3
82 (0)
1
1
1
3
4
5
Au(PPh
---
)Cl
0
0
0
0
0
(>99)
(0)
AgOTf
---
0
TfOH
TfOH
0
(12)
(0)
16
---
0
a
b1
All reactions conducted in DCE (0.1 M) and analyzed after 24 h. H NMR yields determined using dibenzyl
c
d
ether as an internal standard. DCE (0.2 M) 1 equiv. of water added.
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Having established the identity of the para-alkoxy group as a critical structural feature of the substrate with
regard to product selectivity, we screened alternative reaction conditions in search of further improvements
(Table 2). Changes in the reaction temperature (entry 1), concentration (entries 3 & 5), and the identity of the
silver salt activator (entries 6-8) all failed to improve the yield of 13.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
The commercially available cationic gold complex Au(XPhos)SbF •MeCN, which we had previously found
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
to be a far superior catalyst to the combination of Au(PPh
3
)Cl and AgOTf for the ortho-cyclization N-aryl
8
alkynamides, gave inferior results for the ipso-cyclization reaction (entries 9-11). Interestingly, when we ran
the reaction in the presence of water (entry 12), we found a reversal of selectivity back to the β-ketoamide 17,
indicating that the lability of the tert-butyl group alone is not enough to achieve ipso-cyclization.
In the absence of a silver salt activator, the reaction of 16 with 5 mol % AuPPh
3
Cl gave no reaction after 24 h
9
at 80 °C (entry 13). Given that triflic acid can be formed by the reaction of AgOTf with DCE, we ran the
3
reaction in absence of AuPPh Cl to test if hidden Brønsted acid catalysis could be responsible for either the
ipso-cyclization altogether or the cleavage of the tert-butyl ether linkage in situ, which would generate the para-
1
hydroxy substrate analog. Analysis of the crude reaction mixture by H NMR showed complete loss of the tert-
butyl group in 4 h (Scheme 1). While we did not observe any spirolactam or β-ketoamide formation, all of the
starting material was consumed. The major product of the reaction was the para-hydroxy N-aryl alkynamide 18
formed in 68% yield from 16 by cleavage of the tert-butyl ether. In addition, 4-hydroxyaniline was formed in
27% yield, presumably by subsequent hydrolysis of 18. Analysis of the reaction mixture after 24 h showed no
further change. The liberation of the tert-butyl cation was also supported by the presence of isobutylene and
tert-butanol in the spectrum.
Scheme 1. tert-Butyl ether cleavage by AgOTf in DCE
Me
Me
Me
Me
tBuO
HO
HO
AgOTf 5 mol %
DCE, 80 ºC
N
H
O
N
H
O
NH
2
OH
1
6
18
27%
68%
all observed by crude 1H NMR
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Finally, we subjected 16 to 5 mol % triflic acid in DCE at both 50 °C and 80 °C (entries 15 & 16). The
reaction run at 50 °C contained 12% unreacted starting material, along with a 62% yield of 18. The reaction run
at 80 °C led to a more complex mixture. However, the para-hydroxy amide 18 (55%) was clearly detected,
along with 5% of 4-hydroxyaniline; no starting material remained. Neither the spirolactam 13, nor the β-
ketoamide 17 were observed.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
Collectively, these results suggest that both AuPPh Cl and AgOTf are required to form the active catalyst. In
addition, while AgOTf is capable of catalyzing the cleavage of the tert-butyl ether, either directly or through
Brønsted acid catalysis by triflic acid, the resulting para-hydroxy substrate 18 is not capable undergoing ipso-
cyclization in the resulting reaction mixture. Thus, it would appear that the successful catalytic ipso-cyclization
3
of N-aryl alkynamides requires a highly labile para-alkoxy linkage and both AuPPh Cl and AgOTf.
With our optimized conditions established, we began to investigate the scope of the ipso-cyclization reaction
and prepared a series of substrates with varying substituents at the alkynyl position and around the arene ring
(19a-h, Figure 4). While alkynyl substitution was tolerated, including sterically demanding substituents, phenyl
(19b) and cyclohexyl (19d), the yields of the spirolactams were significantly lower and complex mixtures of
byproducts that could not be identified were observed. There was a greater tolerance for substitution around the
arene ring. The yields for ipso-cyclization of both electron- poor (19e, 19f) and –rich (19g, 19h) arenes were
moderate to good. Substrate 19h is particularly noteworthy for the tolerance of an ortho-substituent.
R
O
R
tBuO
FG
FG
3
Au(PPh )Cl 5 mol %
AgOTf 5 mol %
DCE, 80 ºC
HN
N
H
O
O
1
9a-h
20a-h
O
H
O
O
O
HN
1% (20a)
HN
64% (20b)
HN
37% (20c)
HN
57% (20d)
O
O
O
O
4
O
Me
O
O
Me
O
Me
Me
F
F
3
C
Me
HN
0% (20e)
HN
HN
HN
MeO
O
O
O
O
7
78% (20f)
74% (20g)
85% (20h)
Figure 4. Investigation of para-tert-butoxy substrates
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We next investigated a series of substrates bearing N-substitution. Given the general structure of our target
substrates we employed an Ugi four-component reaction strategy to synthesize a series of compounds (21a-c,
Figure 5) that not only exhibited N-substitution, but were more complex than those we had previously tested.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Related substrates, with a para-methoxy group in place of our tert-butoxy group, have been shown to under
3f.g
ipso-cyclization using stoichiometric activators or strong Brønsted acids.
Under our established catalytic
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
conditions, the para-tert-butoxy aniline derived Ugi products fared well, giving modest yields of the N-
substituted spirolactams 22a-c.
Ugi Four-Component Reaction
Me
tBuO
O
Me
CO H
tBuO
21a-c
O
2
R
NC
DCE, rt
R'
NH2
N
O
O
R'
R
NH
spirocyclization products:
O
Me
O
Me
O
Me
N
N
N
Ph
Ph
Ph
O
O
O
O
O
N
H
N
H
N
H
76% (22a)
65% (22b)
68% (22c)
Figure 5. Synthesis and spirocyclization of N-substituted para-tert-butoxy substrates
Our final investigation of substrate scope was inspired by the in situ formation of para-hydroxy amide 18 we
observed in our control experiments. Since both AgOTf and TfOH were incapable of catalyzing the ipso-
cyclization of this compound, we were interested to see if our optimized conditions could yield the desired
spirolactam product. Given the absence of an alkyl group on the para-substituent, we anticipated that this
substrate class would be highly reactive. Several para-hydroxy substrates (18, 23a-f, Figure 6) were prepared in
good yields by selective amine acylation of the para-hydroxyaniline precursors.
Overall, these substrates performed very well and delivered the spirolactams (13, 24a-f) in good yields
(Figure 6). Given the higher reactivity of this substrate class we were able to decrease the reaction temperature
from 80 °C to 50 °C. Experiments run at ambient temperature did provide some product, however, the low
solubility of the substrates in DCE led to dramatic decreases in reaction rate, which ultimately culminated in
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stalled reactions. Thus, the necessity to heat these reactions is due more so to solvation issues, rather than the
inherent reactivity of the substrates themselves. Again, substrates bearing N-substitution (23a), and both
electron-withdrawing (23b) and –donating (23c) substituents were well tolerated. The selective ipso-cyclization
of substrate 23c was somewhat surprising given the increased electron density imparted to the ortho-positions
of the amide. We suspected that ortho-cyclization leading to a 2-quinonlinone product might become a
competitive, if not dominant, mode of cyclization for this substrate. However, no 2-quinolinone was detected.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Me
O
FG
Me
O
HO
FG
Au(PPh3)Cl 5 mol %
AgOTf 5 mol %
DCE, 50 ºC
HN
N
H
O
1
8, 23a-f
13, 24a-f
O
Me
O
Me
O
Me
O
O
Me
O
Cl
MeO
HN
O
N
HN
HN
Me
O
74% (13)
77% (24a)
76% (24b)
84% (24c)
Me
Cl
O
Me
O
Me
O
O
Me
O
10 mol % catalyst
52% conversion
7% yield brsm
Me
Cl
6
HN
HN
HN
Me
O
8
4% (24d)
83% (24e)
35% (24f)
Figure 6. para-Hydroxy substrate investigation
The dichloro substrate 23f was the one outlier in this series. When we analyzed the reaction mixture by GC-
1
MS and H NMR after 24 h, only a small amount of spirolactam 24f was detected. In addition to significant
unreacted starting material, we also observed the amide hydrolysis product 3,5-dichloro-4-hydroxyaniline.
Increasing the reaction temperature to 80 °C led to complete conversion of the starting material, when analyzed
after 24 h, however, the only identifiable product was 3,5-dichloro-4-hydroxyaniline. We re-ran the experiment
at 80 °C, this time carefully monitored the progress by GC-MS. We found that after the first 5 h, the product
began to decompose at a rate faster than its formation. Increasing the catalyst loading to 10 mol % and stopping
the reaction at 5 h allowed us to isolate spirolactam 24f in 35% yield, along with 48% unreacted starting
material.
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The final substrate in this series was the aminonaphthol derived N-aryl alkynamide 25 (Scheme 2). This
substrate proved to be exceptionally reactive, with complete conversion of 25 achieved in 1 h, to give an 85%
yield of the benzo-fused spirolactam 26.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 2. Naphthyl Derived Substrate Spirocyclization
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OH
O
3
Au(PPh )Cl 5 mol %
8
5% yield
1 hour
AgOTf 5 mol %
DCE, 50 ºC
Me
Me
NH
O
HN
2
6
2
5
O
Conclusion:
In summary, we have developed a catalytic method for the ipso-cyclization of N-aryl alkynamides, affording
spirolactams in moderate to good yields. The successful ipso-cyclization of this substrate class is heavily
dictated by the identity of the substituent para to the alkynamide side-chain. The presence of an alkoxy-group
capable of liberating a stable cation is critical to promoting cyclization over hydration of the alkyne.
Alternatively, exchanging the para-alkoxy group for a hydroxy group yields a class of substrates with increased
reactivity, granting access to a wider range of spirolactams from readily accessible starting materials.
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The Journal of Organic Chemistry
Experimental Section:
General Comments
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
All manipulations of air and/or water sensitive compounds were performed using standard Schlenk techniques.
Nitrogen was purified by passage through Drierite. Nuclear Magnetic Resonance spectra were recorded at 300
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
K on a Bruker 300 MHz Fourier transform spectrometer. H NMR spectra recorded in CDCl
3
were referenced to
TMS (0.00 ppm). Spectra in DMSO-d
6
were referenced to the solvent residual peak (2.50 ppm). 13C{1H}
NMR recorded in CDCl or DMSO-d were referenced to the residual solvent peak (77.16 ppm and 39.52 ppm
3
6
respectively). Manual flash column chromatography was conducted on SILICYCLE silica gel (230-400 mesh).
Automated flash column chromatography was conducted on a Teledyne ISCO CombiFlash Rf+ system, using
RediSep Rf normal-phase silica flash columns. Mass spectra were recorded on a Waters Q-TOF Ultima ESI by
the Mass Spectrometry Laboratory of the University of Illinois at Urbana-Champaign. Reactions were
monitored by TLC analysis using EtOAc/hexanes mixtures as the eluent and visualized using UV light followed
by potassium permanganate stain and/or ceric ammonium molybdate stain.
Part 1. General Procedures for Substrate Synthesis:
Method A - General procedure for the DIC mediated synthesis of N-aryl alkynamide substrates: Substrates
were prepared by the DIC mediated coupling of the desired aniline derivative with the chosen alkynoic acid
6
,8
catalyzed by DMAP, according to the previously reported conditions.
Method B - General procedure for the isopropyl chloroformate mediated synthesis of N-aryl alkynamides
substrates: Substrates were prepared by reaction of the desired aniline derivative (1.0 equiv) with the mixed
carbonic acid anhydride (1.5 equiv) prepared from the chosen alkynoic acid (1.5 equiv) and isopropyl
chloroformate (1.5 equiv) with N-methyl morpholine (1.5 equiv) in ethyl acetate [0.8 M], according to the
6,8
previously reported conditions.
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Method C - General procedure for the synthesis of N-substituted N-aryl alkynamides substrates via the Ugi
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
0
four component reaction: para-tert-Butoxy aniline (1 equiv) was weighed into a round-bottom flask. DCE
(0.08 M) was added, followed by the desired aldehyde (1 equiv). The mixture was stirred with a magnetic stir
bar at room temperature for 10 minutes, after which 2-butynoic acid (1 equiv) and the desired isocyanide (1
equiv) were added. The mixture was stirred overnight at room temperature. Celite was added to the flask and
the solvent was removed by rotary evaporation. The product was then purified by column chromatography to
afford the pure amide substrates.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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The Journal of Organic Chemistry
Part 2. Synthesis and Characterization of N-Aryl Alkynamide Substrates:
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
N-(4-Methoxyphenyl)but-2-ynamide (10). Method B was followed, using 2-butynoic acid (567.0 mg, 6.7 mmol)
and p-anisidine (554.2 mg, 4.5 mmol). Extractive work-up followed by automated flash column
chromatography on silica gel eluting with a gradient of 0-50% EtOAc/Hex afforded pure amide 10 (544 mg,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
6
4%) as an amorphous white solid. H NMR (CDCl , 300 MHz) δ 8.14 (s, 1H), 7.46 (d, J = 8.7 Hz, 2H), 6.83
3
(
d, J = 8.7 Hz, 2H), 3.77 (s, 3H), 1.92 (s, 3H); 13C{1H} NMR (CDCl , 75 MHz) δ 156.6, 151.4, 130.8, 121.8,
3
-
1
114.1, 84.3, 75.4, 55.5, 3.7; FT-IR (cm ) 3270, 3249, 3133, 3073, 3009, 2914, 2240, 1636, 1601, 1548, 1509,
+
1
414, 1241, 1029; HRMS (ES+) m/z calcd. for C H NO [M+H] 190.0868, found 190.0871.
1
1
12
2
N-(4-(tert-Butoxy)phenyl)but-2-ynamide (16). Method B was followed, using 2-butynoic acid (1.70 g, 20.25
1
1
mmol) and 4-tert-butoxyaniline (2.230 g, 13.5 mmol), which was prepared by following known procedure.
Following complete consumption of the starting material the solution was washed with 10% HCl (aq), followed
by saturated NaHCO (aq), and dried over MgSO . The mixture was filtered, and the volume of the filtrate was
3
4
reduced by rotary evaporation until precipitation of the product began. The precipitation was further promoted
by scratching the walls of the flask with a spatula. The mixture was filtered, and the solid was washed with
1
hexanes and dried under vacuum to afford pure amide 16 (1.62 g, 78%) as a beige amorphous solid. H NMR
(
CDCl , 300 MHz) δ 7.98 (bs, 1H), 7.44 (d, J = 9 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 1.94 (s, 3H), 1.31 (s, 9H);
3
-
1
13C{1H} NMR (CDCl , 75 MHz) δ 152.0, 151.2, 133.2, 124.7, 120.8, 84.5, 78.8, 75.4, 28.8, 3.8; FT-IR (cm )
3
3
264, 3120, 3053, 2978, 2928, 2236, 1642, 1600, 1535, 1508, 1239, 1161; HRMS (ES+) m/z calcd. for
+
C H NO [M+H] 232.1338, found 232.1354.
14 18
2
N-(4-Hydroxyphenyl)but-2-ynamide (18). Method B was followed, using 2-butynoic acid (378 mg, 4.5 mmol)
and 4-hydroxyaniline (327 mg, 3 mmol). Extractive work-up followed by precipitation and isolation by
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1
filtration afforded pure amide 18 (198 mg, 38%) as an amorphous white solid. H NMR (DMSO-d , 300 MHz)
6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
δ 10.32 (s, 1H), 9.27 (s, 1H), 7.37 (d, J = 9.0 Hz, 2H), 6.69 (d, J = 9.0 Hz, 2H), 2.01 (s, 3H); 13C{1H} NMR
-
1
(DMSO-d , 75 MHz) δ 153.8, 150.1, 130.3, 121.3, 115.1, 83.4, 76.1, 3.2; FT-IR (cm ) 3358, 2237, 1603, 1515,
6
+
1
440, 1258; HRMS (ES+) m/z calcd. for C H NO [M+H] 176.0712, found 176.0720.
1
0
10
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N-(4-(tert-Butoxy)phenyl)propiolamide (19a). Method A was followed, using propiolic acid (420.3 mg, 6
mmol) and 4-tert-butoxyaniline (661 mg, 4 mmol). Extractive work-up followed by automated flash column
chromatography on silica gel eluting with a gradient of EtOAc/Hex 0-40% afforded pure amide 19a (284 mg,
1
3
3%) as an amorphous beige solid. H NMR (CDCl
3
, 300 MHz) δ 7.54 (bs, 1H), 7.41 (d, J = 8.7 Hz, 2H), 6.96
, 75 MHz) δ 152.5, 149.8, 132.7, 124.8,
(d, J = 8.7 Hz, 2H), 2.92 (s, 1H), 1.33 (s, 9H); 13C{1H} NMR (CDCl
3
-
1
1
1
21.0, 79.0, 74.2, 28.9; FT-IR (cm ) 3274, 3119, 3056, 2979, 2111, 1650, 1602, 1535, 1506, 1407, 1366, 1232,
+
160; HRMS (ES+) m/z calcd. for C13
H16NO
2
[M+H] 218.1181, found 218.1174.
N-(4-(tert-Butoxy)phenyl)-3-phenylpropiolamide (19b). Method B was followed, using phenylpropiolic acid
(658 mg, 4.5 mmol) and 4-tert-butoxyaniline (496 mg, 3 mmol). Extractive work-up followed by automated
flash column chromatography on silica gel eluting with a gradient of 0-30% EtOAc/Hex afforded pure amide
1
19b (624 mg, 71%) as an amorphous white solid. H NMR (CDCl , 300 MHz) δ 8.52 (bs, 1H), 7.53 (d, J = 8.7
3
Hz, 2H), 7.48 (d, J = 10.2 Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.27 (t, J = 7.2 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H),
1
8
.30 (s, 9H); 13C{1H} NMR (CDCl , 75 MHz) δ152.2, 151.3, 133.2, 132.6, 130.2, 128.5, 124.7, 120.9, 120.1,
3
-
1
5.9, 83.6, 78.8, 28.8; FT-IR (cm ) 3265, 3188, 3166, 3056, 2977, 2122, 1639, 1603, 1540, 1507, 1408, 1368,
+
1233, 1164; HRMS (ES+) m/z calcd. for C H NO [M+H] 294.1494, found 294.1497.
1
9
20
2
N-(4-(tert-Butoxy)phenyl)-3-cyclopropylpropiolamide (19c). Method
B
was followed, using 3-
cyclopropylpropiolic acid (330 mg, 3 mmol) and 4-tert-butoxyaniline (330 mg, 2 mmol). Extractive work-up
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The Journal of Organic Chemistry
followed by automated flash column chromatography on silica gel eluting with a gradient of EtOAc/Hex 0-40%
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
afforded pure amide 19c (314 mg, 61%) as an amorphous beige solid. H NMR (CDCl
3
, 300 MHz) δ 7.49 (bs,
1H), 7.39 (d, J = 9 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 1.32 (m, 10H; the 9H of the tert-butyl are eclipsing the 1H
3
of the cyclopropyl methine), 0.93-0.88 (m, 4H); 13C{1H} NMR (CDCl , 75 MHz) δ 152.0, 151.2, 133.2, 124.8,
-1
1
20.7, 92.0, 78.8, 71.4, 28.8, 9.07, -0.5; FT-IR (cm ) 3265, 3193, 3112, 3050, 2977, 2219, 1640, 1603, 1537,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
2
1504, 1402, 1361, 1244, 1164; HRMS (ES+) m/z calcd. for C16H20NO [M+H] 258.1494, found 258.1505.
N-(4-(tert-Butoxy)phenyl)-3-cyclohexylpropiolamide (19d). Method
B
was followed, using 3-
11
cyclohexylpropiolic acid (457 mg, 3 mmol) and 4-tert-butoxyaniline (330 mg, 2 mmol). Following complete
consumption of the starting material the solution was washed with 10% HCl (aq), followed by saturated
3 4
NaHCO (aq), and dried over MgSO . The mixture was filtered, and the volume of the filtrate was reduced by
rotary evaporation until precipitation of the product began. The precipitation was further promoted by
scratching the walls of the flask with a spatula. The mixture was filtered, and the solid was washed with
1
hexanes and dried under vacuum to afford pure amide 19d (264 mg, 44%) as an amorphous beige solid. H
NMR (CDCl
3
, 300 MHz) δ 7.63 (bs, 1H), 7.42 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 2.50 (bm, 1H), 1.82
, 75 MHz) δ 152.1, 133.0,
(bm, 2H), 1.73 (bm, 2H), 1.52 (bm, 3H), 1.32 (s, 12H); 13C{1H} NMR (CDCl
3
-
1
124.7, 120.7, 92.1, 78.7, 31.7, 28.9, 28.8, 25.6, 24.8; FT-IR (cm ) 3267, 3115, 3050, 2977, 2931, 2855, 2221,
+
1
2
640, 1602, 1537, 1506, 1407, 1366, 1320, 1238, 1161; HRMS (ES+) m/z calcd. for C19H26NO [M+H]
3
00.1964, found 300.1953.
N-(4-(tert-Butoxy)-3-fluorophenyl)but-2-ynamide (19e). Method B was followed, using 2-butynoic acid (234
mg, 2.79 mmol) and 3-fluoro-4-tert-butoxyaniline (341 mg, 1.86 mmol). Extractive work-up followed by
automated flash column chromatography on silica gel eluting with a gradient of EtOAc/Hex 0-40% afforded
1
pure amide 19e (243 mg, 52%) as an amorphous beige solid. H NMR (CDCl
3
, 300 MHz) δ 8.20 (bs, 1H), 7.53
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(
dd, J = 12 Hz, J = 2.4 Hz, 1H), 7.14 (d, J = 8.7 Hz, 1H), 6.99 (t, J = 8.7 Hz), 1.95 (s, 3H), 1.33 (s, 9H);
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
1
3C{1H} NMR (CDCl , 75 MHz) δ 158.2, 155.0, 151.3, 139.2, 139.1, 134.1, 134.0, 126.9(2), 126.8(9),
3
-
1
115.1(3), 115.0(9), 109.0, 108.7, 85.1, 80.8, 75.2, 28.4, 3.7; FT-IR (cm ) 3251, 3117, 3091, 3053, 2977, 2923,
+
2
358, 2339, 2230, 1643, 1596, 1418, 1367, 1116; HRMS (ES+) m/z calcd. for C14
H17FNO
2
[M+H] 250.1243,
found 250.1249.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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8
9
0
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2
3
4
5
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7
8
9
0
N-(4-(tert-Butoxy)-3-(trifluoromethyl)phenyl)but-2-ynamide (19f). Method B was followed, using 2-butynoic
acid (239 mg, 2.85 mmol) and 3-trifluoromethyl-4-tert-butoxyaniline (433 mg, 1.90 mmol). Extractive work-up
followed by automated flash column chromatography on silica gel eluting with a gradient of EtOAc/Hex 30-
1
80% afforded pure amide 19f (243 mg, 43%) as an amorphous white solid. H NMR (CDCl , 300 MHz) δ 7.71
3
(dd, J = 9.0 Hz, J = 2.4 Hz, 1H), 7.56 (d, J = 2.7 Hz, 1H), 7.44 (bs, 1H), 7.16 (d, J = 9.0 Hz, 1H), 2.00 (s, 3H),
1
.45 (s, 9H); 13C{1H} NMR (CDCl , 75 MHz) δ 151.9, 151.7, 131.4, 125.2, 124.5, 123.5, 123.1, 121.5, 119.2,
3
-
1
119.1, 85.3, 80.9, 75.0, 29.1, 3.6; FT-IR (cm ) 3434, 2988, 2938, 2240, 2149, 1643, 1544, 1450, 1429, 1324,
+
1
254, 1163, 1133, 1051; HRMS (ES+) m/z calcd. for C H F NO [M+H] 300.1211, found 300.1209.
1
5
17
3
2
N-(4-(tert-Butoxy)-3-methylphenyl)but-2-ynamide (19g). Method B was followed, using 2-butynoic acid (295
mg, 3.51 mmol) and 3-methyl-4-tert-butoxyaniline (419 mg, 2.34 mmol). Extractive work-up followed by
automated flash column chromatography on silica gel eluting with a gradient of EtOAc/Hex 0-40% afforded
1
pure amide 19g (384 mg, 67%) as a viscous brown oil. H NMR (CDCl
3
, 300 MHz) δ 7.29 (d, J = 2.7 Hz, 1H),
7
.21 (dd, J = 8.7 Hz, J = 2.7 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H) 2.22 (s, 3H) 2.00 (s, 3H), 1.36 (s, 9H); 13C{1H}
3
NMR (CDCl , 75 MHz) δ 151.3, 151.1, 133.0, 132.2, 122.9, 122.6, 118.1, 84.2, 79.4, 75.6, 29.2, 17.5, 3.9; FT-
-1
IR (cm ) 3267, 3120, 3065, 2981, 2926, 2236, 1639, 1543, 1499, 1415, 1367, 1253, 1173; HRMS (ES+) m/z
+
calcd. for C15
H20NO
2
[M+H] 246.1494, found 246.1485.
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N-(4-(tert-Butoxy)-3-methoxyphenyl)but-2-ynamide (19h). Method B was followed, using 2-butynoic acid (221
mg, 2.63 mmol) and 2-methoxy-4-tert-butoxyaniline (1.75 mmol). Extractive work-up followed by automated
1
2
3
4
5
6
7
8
9
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1
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5
5
5
6
flash column chromatography on silica gel eluting with a gradient of EtOAc/Hex 0-60% afforded pure amide
1
1
9h (376 mg, 82%) as amorphous white solid. H NMR (CDCl
3
, 300 MHz) δ 8.18 (d, J = 9.0 Hz, 1H), 7.84 (bs,
1
H), 6.64 (d, J = 2.7 Hz, 1H), 6.59 (dd, J = 9.0 Hz, J = 3.0 Hz, 1H), 3.77 (s, 3H), 2.01 (s, 3H), 1.43 (s, 9H);
, 75 MHz) δ 156.1, 150.6, 145.5, 125.7, 121.4, 108.8, 107.6, 83.8, 81.3, 75.8, 55.7, 29.2,
0
1
2
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4
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8
9
0
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3
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13C{1H} NMR (CDCl
3
-
1
4
.0; FT-IR (cm ) 3241, 2916, 2844, 2243, 1636, 1593, 1525, 1307; HRMS (ES+) m/z calcd. for C15H20NO
3
+
[
M+H] 262.1443, found 262.1440.
Amide 21a. Method C was followed, using 4-tert-butoxyaniline (100 mg, 0.61 mmol), 2-butynoic acid (54 mg,
0
.61 mmol), tert-butyl isocyanide (51 mg, 0.61 mmol), and benzaldehyde (65 mg, 0.61 mmol). Extractive work-
up followed by automated flash column chromatography on silica gel eluting with a gradient of EtOAc/Hex 0-
1
4
0% afforded pure amide 21a (122 mg, 48%) as an amorphous white solid. H NMR (CDCl
3
, 300 MHz) δ 7.18-
7.14 (m, 5H), 7.02 (bd, J = 6.3 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 5.93 (s, 1H), 5.71 (bs, 1H), 1.66 (s, 3H), 1.34
s, 9H), 1.27 (s, 9H); 13C{1H} NMR (CDCl , 75 MHz) δ 168.3, 155.2, 155.1, 135.1, 134.3, 131.3, 130.5,
(
3
-
1
1
28.4, 128.3, 123.9, 91.1, 78.9, 74.2, 65.2, 51.7, 28.8, 28.7, 3.8; FT-IR (cm ) 3315, 3065, 2971, 2915, 2870,
+
33 2 3
2249, 1679, 1617, 1504, 1361, 1159; HRMS (ES+) m/z calcd. for C26H N O [M+H] 421.2491, found
4
21.2472.
Amide 21b. Method C was followed, using 4-tert-butoxyaniline (100 mg, 0.61 mmol), 2-butynoic acid (54 mg,
0
.61 mmol), cyclohexyl isocyanide (67 mg, 0.61 mmol), hydrocinnamaldehyde (82 mg, 0.61 mmol). Extractive
work-up followed by automated flash column chromatography on silica gel eluting with a gradient of
1
EtOAc/Hex 0-40% afforded pure amide 21b (107 mg, 37%) as an amorphous beige solid. H NMR (CDCl
3
, 300
MHz) δ 7.24-7.13 (m, 5H), 7.07 (d, J = 6.9 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 6.54 (d, J = 8.1 Hz, 1H), 4.94 (t, J
=
7.5 Hz, 1H), 3.85-3.75, (m, 1H), 2.68-2.50 (m, 2H), 2.00-1.91 (m, 2H), 1.71-1.57 (m, 9H; the alkynyl methyl
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peak is eclipsed by eight of the cyclohexyl protons), 1.36 (s, 9H), 1.28-1.21 (m, 3H); 13C{1H} NMR (CDCl
3
,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
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2
2
2
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2
2
2
2
2
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4
4
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5
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5
6
7
5 MHz) δ 169.1, 155.9, 155.7, 141.0, 133.5, 130.1, 128.4, 126.1, 124.0, 92.1, 79.1, 73.9, 58.0, 48.2, 32.8, 32.4,
-
1
30.2, 28.8, 25.5, 24.7(1), 24.6(5), 3.82; FT-IR (cm ) 3326, 2973, 2926, 2854, 2249, 1619, 1536, 1504, 1366,
+
1
326, 1160; HRMS (ES+) m/z calcd. for C30
H
39
N
2
O
3
[M+H] 475.2961, found 475.2961.
ꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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8
9
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9
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9
0
Amide 21c. Method C was followed, using 4-tert-butoxyaniline (100 mg 0.61 mmol), 2-butynoic acid (54 mg,
0
.61 mmol), cyclohexyl isocyanide (67 mg, 0.61 mmol), and benzaldehyde (65 mg, 0.61 mmol). Extractive
work-up followed by automated flash column chromatography on silica gel eluting with a gradient of
1
EtOAc/Hex 0-40% afforded pure amide 21b (116 mg, 43%) as an amorphous beige solid. H NMR (CDCl
3
, 300
MHz) δ 7.21-7.11 (m, 5H), 7.01 (bd, J = 6.9 Hz, 2H), 6.78 (d, J = 8.1 Hz, 2H), 6.03 (s, 1H), 5.64 (d, J = 7.2 Hz,
H), 3.88-3.77, (m, 1H), 1.96 (bd, J = 10.5 Hz, 1H), 1.84 (bd, J = 11.7 Hz, 1H), 1.71-1.55 (m, 5H), 1.42-1.31
1
(m, 3H), 1.28 (s, 9H), 1.19-1.05 (m, 3H); 13C{1H} NMR (CDCl
3
, 75 MHz) δ 168.2, 155.3, 155.2, 135.1, 134.3,
-
131.4, 130.5, 128.6, 128.4, 124.0, 91.2, 79.0, 74.2, 64.7, 48.9, 32.9, 28.9, 25.6, 24.9, 24.8, 3.9; FT-IR (cm
1
)
35 2 3
3296, 2974, 2928, 2851, 2254, 1661, 1636, 1505, 1367, 1152; HRMS (ES+) m/z calcd. for C28H N O
+
[
M+H] 447.2648, found 447.2639.
N-(4-Hydroxyphenyl)-N-methylbut-2-ynamide (23a). Method B was followed, using 2-butynoic acid (378 mg,
4
.5 mmol) and (4-methylamino)phenol hemisulfate (517mg, 3 mmol). Extractive work-up followed by
precipitation and isolation by filtration afforded pure amide 23a (261 mg, 46%) as an amorphous white solid.
Spectroscopic analysis revealed this product to be a mixture of atropisomers. The data reported here is for the
1
major isomer. H NMR (DMSO-d , 300 MHz) δ 9.64 (bs, 1H), 7.12 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 8.1 Hz,
6
2
7
H), 3.12 (s, 3H), 1.74 (s, 3H); 13C{1H} NMR (DMSO, 75 MHz) δ 156.7, 153.3, 134.3, 128.4, 115.5, 89.3,
-
1
4.4, 36.2, 3.2; FT-IR (cm ) 3182, 2917, 2230, 1615, 1514, 1448, 1390, 1266, 1234, 1168, 1099; HRMS (ES+)
+
m/z calcd. for C H NO [M+H] 190.0868, found 190.0862.
1
1
12
2
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The Journal of Organic Chemistry
1
2
3
N-(3-Chloro-4-hydroxyphenyl)but-2-ynamide (23b). Method B was followed, using 2-butynoic acid (378 mg,
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
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5
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5
5
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5
6
4
.5 mmol) and 3-chloro-4-hydroxyaniline (431 mg, 3 mmol). Extractive work-up followed by precipitation and
1
isolation by filtration afforded pure amide 23b (448 mg, 71%) as an amorphous white solid. H NMR (DMSO-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
d6, 300 MHz) δ 10.53 (s, 1H), 10.05 (s, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 8.7 Hz, J = 2.4 Hz, 1H),
6
.93 (d, J = 9.0 Hz, 1H), 2.06 (s, 3H); 13C{1H} NMR (DMSO-d , 300 MHz) δ 150.2, 149.4, 131.0, 121.0,
6
-
1
119.6, 119.1, 116.5, 84.1, 75.8, 3.2; FT-IR (cm ) 3319, 3127, 2234, 1626, 1595, 1549, 1493, 1263; HRMS
+
(ES+) m/z calcd. for C H ClNO [M+H] 210.0322, found 210.0314.
1
0
9
2
N-(4-Hydroxy-3-methoxyphenyl)but-2-ynamide (23c). Method B was followed, using 2-butynoic acid acid
(378 mg, 4.5 mmol) and 3-methoxy-4-hydroxyaniline (417 mg, 3 mmol). Extractive work-up followed by
1
precipitation and isolation by filtration afforded pure amide 23c (418 mg, 68%) as an amorphous white solid. H
NMR (DMSO-d , 300 MHz) δ 10.34 (s, 1H), 8.83 (s, 1H), 7.29 (s, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.71 (d, J =
6
8
1
.1 Hz, 1H), 3.75 (s, 3H), 2.05 (s, 3H); 13C{1H} NMR (DMSO-d :CDCl (3:1), 300 MHz) δ 150.0, 147.2,
6 3
-
1
43.0, 130.7, 115.1, 112.2, 105.0, 83.2, 76.1, 55.5, 3.2; FT-IR (cm ) 3295, 2938, 2234, 1621, 1516, 1274;
+
HRMS (ES+) m/z calcd. for C H NO [M+H] 206.0817, found 206.0821.
1
1
12
3
N-(4-Hydroxy-2-methylphenyl)but-2-ynamide (23d). Method B was followed, using 2-butynoic acid (252 mg, 3
mmol) and 2-methyl-4-hydroxyaniline (246 mg, 2 mmol). Extractive work-up followed by automated flash
column chromatography on silica gel eluting with a gradient of EtOAc/Hex 0-60% afforded pure amide 23d
1
(185 mg, 49%) as an amorphous tan solid. H NMR (DMSO-d , 300 MHz) δ 9.72 (s, 1H), 9.29 (s, 1H), 6.96 (d,
6
J = 8.7 Hz, 1H), 6.59 (d, J = 2.7 Hz, 1H), 6.54 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 2.06 (s, 3H), 2.01 (s 3H);
1
3C{1H} NMR (DMSO, 75 MHz) δ 155.5, 151.3, 134.4, 127.3, 126.5, 116.6, 112.7, 83.3, 75.9, 17.9, 3.2; FT-
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-
1
IR (cm ) 3203, 2975, 2923, 2239, 1586, 1528, 1503, 1454, 1424, 1300, 1220; HRMS (ES+) m/z calcd. for
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
C H NO [M+H] 190.0868, found 190.0877.
1
1
12
2
N-(4-Hydroxy-3,5-dimethylphenyl)but-2-ynamide (23e). Method B was followed, using 2-butynoic acid (378
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mg, 4.5 mmol) and 3,5-dimethyl-4-hydroxyaniline (412 mg, 3 mmol). Extractive work-up followed by
1
precipitation and isolation by filtration afforded pure amide 23e (340 mg, 56%) as an amorphous white solid. H
NMR (DMSO-d , 300 MHz) δ 10.24 (s, 1H), 8.12 (s, 1H), 7.17 (s, 1H), 2.15 (s, 6H), 2.05 (3H); 13C{1H} NMR
6
-
1
(
DMSO-d , 75 MHz) δ 150.0, 149.6, 130.3, 124.4, 119.9, 83.3, 76.2, 16.8, 3.2; FT-IR (cm ) 3233, 3034, 2956,
6
+
2
916, 2852, 2231, 1623, 1538, 1483, 1284, 1200; HRMS (ES+) m/z calcd. for C H NO [M+H] 204.1025,
1
2
14
2
found 204.1021.
N-(3,5-Dichloro-4-hydroxyphenyl)but-2-ynamide (23f). Method B was followed, using 2-butynoic acid (378
mg, 4.5 mmol) and 3,5-dichloro-4-hydroxyaniline (534 mg, 3 mmol). Extractive work-up followed by
1
precipitation and isolation by filtration afforded pure amide 23f (322 mg, 44%) as an amorphous white solid. H
NMR (CDCl , 300 MHz) δ 7.49 (s, 2H), 7.31 (bs, 1H), 5.76 (s, 1H), 2.01 (s, 3H); 13C{1H} NMR (CDCl , 300
3
3
-1
MHz) δ 151.0, 145.2, 130.7, 121.3, 120.2, 85.6, 75.0, 4.0; FT-IR (cm ) 3272, 2238, 1642, 1492, 1271, 1162;
+
HRMS (ES+) m/z calcd. for C H Cl NO [M+H] 243.9932, found 243.9940.
1
0
8
2
2
N-(4-Hydroxynaphthalen-1-yl)but-2-ynamide (25). Method B was followed, using 2-butynoic acid (378 mg,
4
.5 mmol) and 4-amino-naphthalen-1-ol (478 mg, 3 mmol). Extractive work-up followed by precipitation and
1
isolation by filtration afforded pure amide 25 (409 mg, 61%) as an amorphous brown solid. H NMR (DMSO-
d6, 300 MHz) δ 10.27 (s, 1H), 10.23 (s, 1H), 8.14 (dd, J = 8.4 Hz, J = 1.2 Hz, 1 H), 7.78 (d, J = 7.8 Hz, 1H),
7
.55-7.44 (apparent multiplet, 2H), 7.25 (d, J = 8.1 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 2.06 (s, 3H); 13C{1H}
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NMR (DMSO, 75 MHz) δ 157.2, 157.1, 135.0, 131.5, 129.9(3), 129.8(9), 129.5, 128.7, 127.9, 127.5, 112.4,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
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4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-
1
8
9.0, 81.1, 8.4; FT-IR (cm ) 3289, 3149, 2236, 1610, 1577, 1307, 1274; HRMS (ES+) m/z calcd. for C H NO
14 12 2
+
[M+H] 226.0868, found 226.0866.
0
1
2
3
4
5
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7
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9
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Part 3. General Spirocyclization Procedure for N-Aryl Alkynamides:
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6
To a 4 mL vial was added AgOTf (5 mol %), followed by Au(PPh )Cl (5 mol %) and a Teflon coated micro stir
3
bar. Bench-top DCE (0.1 M) was then added and the mixture was set to stir at room temperature for 2 minutes.
Lastly the N-aryl alkynamide substrate was added and the vial was capped with a Teflon lined screw cap and set
to stir at room temperature or placed into an aluminum heating block pre-heated to 50 or 80 ºC. Upon complete
consumption of the starting material as judged by TLC (developing with mixtures of EtOAc in hexanes) or GC-
MS the vial was cooled to room temperature. The reaction mixture was concentrated onto Celite via rotary
evaporation and chromatographed by flash column chromatography on silica gel eluting with mixtures of
EtOAc and hexanes.
0
1
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9
0
1
2
3
4
5
6
7
8
9
0
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The Journal of Organic Chemistry
Part 4. Characterization of Products:
1
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
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2
2
2
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3
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3
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5
5
6
N-(4-(methoxy)phenyl)-3-oxobutanamide (12). A modification of the General Spirocyclization Procedure was
followed. Into a 4 mL vial was added AgOTf (2.6 mg, 5 mol %), Au(PPh )Cl (4.9 mg, 5 mol %), a Teflon
3
coated micro stir bar, DCE (2 mL, 0.1M), and water (3.6 uL, 0.2 mmol, 1 equiv.). The mixture was stirred
vigorously at room temperature for 2 minutes, after which the amide substrate 10 (38 mg, 0.2 mmol) was added.
Upon consumption of the starting material the reaction was concentrated onto Celite and purified via automated
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
flash column chromatography on silica gel eluting with a gradient of 0-70% EtOAc/Hex to afford 12 (33.5 mg,
1
8
1%) as an amorphous white solid. H NMR (CDCl , 300 MHz) δ 9.02 (bs, 1H), 7.43 (d, J = 7.5 Hz, 2H), 6.85
3
(d, J = 7.5 Hz, 2H), 3.78 (s, 3H), 3.56 (s, 2H), 2.31 (s, 3H); 13C{1H} NMR (CDCl , 75 MHz) δ 205.3, 163.7,
3
-
1
156.7, 130.7, 122.1, 114.2, 55.5, 49.9, 31.3; FT-IR (cm ) 3249, 3135, 3076, 2956, 2922, 1717, 1652, 1607,
+
1
547, 1518, 1410, 1320, 1283, 1180, 1035; HRMS (ES+) m/z calcd. for C H NO [M+H] 208.0974, found
1
1
14
3
2
08.0972.
4
-Methyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (13). The General Spirocyclization Procedure was
followed at 80 ºC using amide substrate 16 (46 mg, 0.2 mmol). Upon consumption of the starting material, as
determined by GC-MS, the reaction mixture was concentrated onto Celite via rotary evaporation and
chromatographed by automated flash column chromatography on silica gel eluting with a gradient of 20-80%
1
EtOAc/Hex to afford 13 (30.5 mg, 87%) as a white amorphous solid. H NMR (DMSO-d , 300 MHz) δ 8.57 (s,
6
1
H), 6.64 (dd, J = 11.1 Hz, J = 3.0 Hz, 2H), 6.35 (dd, J = 11.1 Hz, J = 3.0 Hz, 2H), 6.10 (t, J = 1.5 Hz, 1H),
.73 (d, J = 1.2 Hz, 3H); 13C{1H} NMR (DMSO-d , 75 MHz) δ 184.5, 172.5, 157.7, 148.2, 130.1, 125.4, 64.7,
1
6
-
1
+
11.8; FT-IR (cm ) 3400, 3038, 1704, 1668, 1624, 1278, 1178; HRMS (ES+) m/z calcd. for C H NO [M+H]
1
0
10
2
1
76.0712, found 176.0720.
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N-(4-(tert-butoxy)phenyl)-3-oxobutanamide (17). A modification of the General Spirocyclization Procedure
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was followed. Into a 4 mL vial was added AgOTf (2.6 mg, 5 mol %), Au(PPh )Cl (4.9 mg, 5 mol %), a Teflon
3
coated micro stir bar, DCE (2 mL, 0.1M), and water (3.6 uL, 0.2 mmol, 1 equiv.). The mixture was stirred
vigorously at room temperature for 2 minutes, after which the amide substrate 16 (46 mg, 0.2 mmol) was added.
Upon consumption of the starting material the reaction was concentrated onto Celite and purified via automated
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
flash column chromatography on silica gel eluting with a gradient of 0-50% EtOAc/Hex to afford 17 (41 mg,
1
8
2%) as an amorphous white solid. H NMR (CDCl , 300 MHz) δ 9.10 (bs, 1H), 7.43 (d, J = 8.7 Hz, 2H), 6.94
3
(
d, J = 9.0 Hz, 2H), 3.56 (s, 2H), 2.30 (s, 3H), 1.32 (s, 9H); 13C{1H} NMR (CDCl , 75 MHz) δ 205.2, 163.6,
3
-
1
1
52.0, 133.2, 124.8, 121.0, 78.7, 50.0, 31.2, 28.8; FT-IR (cm ) 3304, 3195, 3127, 2976, 2932, 1721, 1664,
+
1545, 1509, 1163; HRMS (ES+) m/z calcd. for C H NO [M+H] 250.1443, found 250.1454.
1
4
20
3
1
-Azaspiro[4.5]deca-3,6,9-triene-2,8-dione (20a). The General Spirocyclization Procedure was followed at
0 ºC using amide substrate 19a (65 mg, 0.3 mmol). Upon consumption of the starting material, as determined
8
by GC-MS, the reaction mixture was concentrated onto Celite via rotary evaporation and chromatographed by
automated flash column chromatography on silica gel eluting with a gradient of 20-70% EtOAc/Hex to afford
1
2
0a (20 mg, 41%) as a white amorphous solid. H NMR (CDCl , 300 MHz) δ 7.34 (bs, 1H), 6.73 (d, J = 4.8 Hz,
3
1H), 6.54 (d, J = 9.9 Hz, 2H), 6.38 (d, J = 9.9 Hz, 2H), 6.33 (d, J = 5.1 Hz, 1H); 13C{1H} NMR (CDCl , 75
3
-
1
MHz) δ 184.2, 173.7, 148.1, 145.1, 131.0, 129.7, 63.1; FT-IR (cm ) 3924, 3091, 1710, 1661, 1619, 1400, 1330,
+
1
176; HRMS (ES+) m/z calcd. for C H NO [M+H] 162.0555, found 162.0552.
9
8
2
4
-Phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (20b). The General Spirocyclization Procedure was
followed at 80 ºC using amide substrate 19b (58 mg, 0.2 mmol). Upon consumption of the starting material, as
determined by GC-MS, the reaction mixture was concentrated onto Celite via rotary evaporation and
chromatographed by automated flash column chromatography on silica gel eluting with a gradient of 20-70%
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The Journal of Organic Chemistry
EtOAc/Hex to afford 20a (30 mg, 64%) as a white amorphous solid. NMR analysis of the product matched the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
k
known literature data.
4-Cyclopropyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (20c). The General Spirocyclization Procedure
was followed at 80 ºC using amide substrate 19c (52 mg, 0.2 mmol). Upon consumption of the starting material,
as determined by GC-MS, the reaction mixture was concentrated onto Celite via rotary evaporation and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
chromatographed by automated flash column chromatography on silica gel eluting with a gradient of 20-80%
1
EtOAc/Hex to afford 20c (15 mg, 37%) as a white amorphous solid. H NMR (CDCl , 300 MHz) δ 6.56 (d, J =
3
9
2
.9 Hz, 2H), 6.44 (d, J = 10.2 Hz, 2H), 6.15 (bs, 1H), 5.65 (t, J = 0.9 Hz, 1H), 1.19-1.12 (m, 1H), 1.07-1.01 (m,
H), 0.74-0.69 (m, 2H); 13C{1H} NMR (CDCl , 75 MHz) δ 184.7, 173.9, 167.6, 146.2, 131.4, 117.5, 65.4,
3
-
1
11.7, 8.4; FT-IR (cm ) 3103, 3057, 2918, 1785, 1645, 1609, 1388, 1280, 1199; HRMS (ES+) m/z calcd. for
+
C H NO [M+H] 202.0868, found 202.0873.
1
2
12
2
4
-Cyclohexyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (20d). The General Spirocyclization Procedure was
followed at 80 ºC using amide substrate 19d (60 mg, 0.2 mmol). Upon consumption of the starting material, as
determined by GC-MS, the reaction mixture was concentrated onto Celite via rotary evaporation and
chromatographed by automated flash column chromatography on silica gel eluting with a gradient of 30-80%
1
EtOAc/Hex to afford 20d (28 mg, 57%) as a white amorphous solid. H NMR (MeOD-d , 300 MHz) δ 6.67 (d,
4
J = 9.9 Hz, 2H), 6.43 (d, J = 9.9 Hz, 2H), 6.15 (s, 1H), 1.84-1.70 (m, 6H), 1.38-1.25 (m, 7H); 13C{1H} NMR
-
1
(
MeOD-d , 75 MHz) δ 185.2, 174.7, 169.2, 146.7, 130.5, 122.8, 65.6, 36.4, 33.4, 25.8, 25.2; FT-IR (cm ) 3098,
4
+
2
928, 2856, 1696, 1669, 1383, 1348; HRMS (ES+) m/z calcd. for C H NO [M+H] 244.1338, found
15 18
2
2
44.1347.
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7
-Methyl-4-fluoro-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (20e). The General Spirocyclization Procedure
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was followed at 80 ºC using amide substrate 19e (50 mg, 0.2 mmol). Upon consumption of the starting material,
as determined by GC-MS, the reaction mixture was concentrated onto Celite via rotary evaporation and
chromatographed by automated flash column chromatography on silica gel eluting with a gradient of 30-80%
1
EtOAc/Hex to afford 20e (27 mg, 70%) as a beige amorphous solid. H NMR (DMSO-d , 300 MHz) δ 8.53 (bs,
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1H), 6.71 (dd, J = 9.9 Hz, J = 2.4 Hz, 1H), 6.54 (dd, J = 12.9 Hz, J = 2.4 Hz, 1H), 6.43 (dd, J = 9.9 Hz, J = 7.2
Hz, 1H), 6.12 (s, 1H), 1.78 (s, 3 H); 13C{1H} NMR (DMSO-d , 75 MHz) δ 177.6 (d, J = 21.7 Hz), 172.1,
6
1
57.6, 153.7 (d, J = 262.9 Hz), 150.0 (d, J = 2.4 Hz), 129.2 (d, J = 3.9 Hz), 125.4, 124.1 (d, J = 12.9 Hz), 65.8
-
1
(d, J = 8.6 Hz), 12.0; FT-IR (cm ) 3265, 3097, 3048, 1658, 1659, 1392, 1168; HRMS (ES+) m/z calcd. for
+
C H FNO [M+H] 194.0617, found 194.0620.
1
0
9
2
4
-Methyl-7-(trifluoromethyl)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (20f). The General Spirocyclization
Procedure was followed at 80 ºC using amide substrate 19f (49 mg, 0.2 mmol). Upon consumption of the
starting material, as determined by GC-MS, the reaction mixture was concentrated onto Celite via rotary
evaporation and chromatographed by automated flash column chromatography on silica gel eluting with a
1
gradient of 30-80% EtOAc/Hex to afford 20f (38 mg, 78%) as a white amorphous solid. H NMR (DMSO-d ,
6
300 MHz) δ 8.62 (bs, 1H), 7.42 (s, 1H) 6.81 (d, J = 8.1 Hz, 1H), 6.48 (d, J = 9.0 Hz, 1H) 6.22 (s, 1H), 1.75 (s,
3
H); 13C{1H} NMR (DMSO-d , 75 MHz) δ 179.4, 172.3, 156.4, 151.5 (d, J = 5.1 Hz), 148.7, 129.9, 129.1 (d,
6
-
1
J = 29.2 Hz) 126.6, 121.4 (quart. J = 271.9 Hz), 64.2, 12.0; FT-IR (cm ) 3276, 3107, 3040, 1685, 1656, 1392,
+
1293, 1152, 1032; HRMS (ES+) m/z calcd. for C H F NO [M+H] 244.0585, found 244.0573.
1
1
9
3
2
4
,7-Dimethyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (20g). The General Spirocyclization Procedure was
followed at 80 ºC using amide substrate 19g (49 mg, 0.2 mmol). Upon consumption of the starting material, as
determined by GC-MS, the reaction mixture was concentrated onto Celite via rotary evaporation and
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The Journal of Organic Chemistry
chromatographed by automated flash column chromatography on silica gel eluting with a gradient of 30-80%
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
EtOAc/Hex to afford 20g (28 mg, 74%) as a beige amorphous solid. H NMR (CDCl , 300 MHz) δ 7.61 (bs,
3
1H), 6.47 (dd, J = 9.9 Hz, J = 2.7 Hz, 1H), 6.41 (d, J = 9.9 Hz, 1H) 6.26 (quart., J = 1.2 Hz, 1H), 6.03 (quart, J
=
1.5 Hz, 1H), 1.94 (d, J = 1.2 Hz, 3H), 1.82 (d, J = 1.2 Hz, 3H); 13C{1H} NMR (CDCl , 75 MHz) δ 185.3,
3
-
1
1
74.0, 159.6, 145.9, 140.9, 138.5, 131.3, 124.8, 65.8, 15.9, 12.5; FT-IR (cm ) 3207, 3101, 2920, 1667, 1398,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
1330, 1121; HRMS (ES+) m/z calcd. for C H NO [M+H] 190.0868, found 190.0872.
1
1
12
2
6
-Methoxy-4-methyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (20h). The General Spirocyclization
Procedure was followed at 80 ºC using amide substrate 19h (53 mg, 0.2 mmol). Upon consumption of the
starting material, as determined by GC-MS, the reaction mixture was concentrated onto Celite via rotary
evaporation and chromatographed by automated flash column chromatography on silica gel eluting with a
1
gradient of 30-90% EtOAc/Hex to afford 20h (35 mg, 85%) as a white amorphous solid. H NMR (CDCl , 300
3
MHz) δ 6.81 (bs, 1H), 6.34 (d, J = 8.4 Hz, 1H), 6.14 (d, J = 9.9 Hz, 1H), 5.95 (s, 1H), 5.62 (s, 1H), 3.84 (s, 3H),
1.81 (s, 3H); 13C{1H} NMR (CDCl , 75 MHz) δ 193.6, 175.6, 171.8, 158.5, 140.0, 125.1, 124.2, 100.2, 71.9,
3
-1
5
6.4, 12.4; FT-IR (cm ) 3173, 3056, 1694, 1655, 1571, 1388, 1228, 1168; HRMS (ES+) m/z calcd. for
+
C H NO [M+H] 206.0817, found 206.0820.
1
1
12
3
Spirolactam 22a. The General Spirocyclization Procedure was followed at 80 ºC using amide substrate 21a
84 mg, 0.2 mmol). Upon consumption of the starting material, as determined by GC-MS, the reaction mixture
(
was concentrated onto Celite via rotary evaporation and chromatographed by automated flash column
chromatography on silica gel eluting with a gradient of 30-80% EtOAc/Hex to afford 22a (55 mg, 76%) as a
1
white amorphous solid. H NMR (CDCl , 300 MHz) δ 7.36-7.30 (m, 5H, partially eclipsed by residual solvent
3
peak), 6.61 (d, J = 9.3 Hz, 1H), 6.41 (d, J = 9.0 Hz, 1H), 6.33 (d, J = 9.6 Hz, 1H), 6.20-6.16 (apparent d due to
overlapping peaks, 2H), 5.78 (bs, 1H), 4.97 (bs, 1H), 1.78 (s, 3H), 1.30 (s, 9H); 13C{1H} NMR (CDCl , 75
3
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Page 28 of 35
MHz) δ 184.5, 168.2, 156.4, 146.0, 135.2, 131.7, 131.4, 129.3, 129.1, 128.8, 125.5, 70.0, 62.4, 51.7, 28.5, 12.5;
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-
1
FT-IR (cm ) 3515, 3325, 3067, 3008, 2968, 1966, 1887, 1815, 1677, 1629, 1542, 1455, 1387, 1340, 1229;
+
HRMS (ES+) m/z calcd. for C H N O [M+H] 365.1865, found 365.1851.
2
2
25
2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Spirolactam 22b. The General Spirocyclization Procedure was followed at 80 ºC using amide substrate 21b
136 mg, 0.28 mmol). Upon consumption of the starting material, as determined by GC-MS, the reaction
(
mixture was concentrated onto Celite via rotary evaporation and chromatographed by automated flash column
chromatography on silica gel eluting with a gradient of 30-80% EtOAc/Hex to afford 22b (76 mg, 65%) as a
1
white amorphous solid. H NMR (CDCl , 300 MHz) δ 7.35 (d, J = 7.5 Hz, 1H), 7.30-7.25 (m, 1H partially
3
eclipsed by residual solvent peak), 7.22-7.15 (m, 3H), 6.51 (dd, J = 9.9 Hz, J = 1.8 Hz, 1H), 6.41 (dd, J = 9.9
Hz, J = 1.5 Hz, 1H), 6.36 (dd, J = 9.9 Hz, J = 3.0 Hz, 1H), 6.28 (dd, J = 10.2 Hz, J = 3.0 Hz, 1H), 6.12 (s, 1H),
3
1
.71 (bm, 1H), 3.68 (t, J = 8.4 Hz, 1H), 2.61 (t, J = 7.5 Hz, 2H), 2.57-2.48 (m, 1H), 2.33-2.26 (m, 1H), 1.87-
.81 (m, 2H eclipsed by methyl singlet at 1.81), 1.81 (s, 3H), 1.71-1.67 (m, 2H partially eclipsed by water),
1.48-1.39 (m, 2H), 1.38-1.21 (m, 4H); 13C{1H} NMR (CDCl , 75 MHz) δ 183.9, 172.6, 157.0, 144.9, 144.1,
3
1
40.5, 133.4, 133.3, 128.7, 128.6, 126.4, 126.0, 70.9, 60.7, 48.1, 33.0, 32.8, 32.1, 25.6, 24.7, 24.6, 12.9; FT-IR
-
1
+
(
cm ) 3304, 3061, 2930, 2857, 1675, 1539, 1363; HRMS (ES+) m/z calcd. for C H N O [M+H] 419.2335,
26 31 2 3
found 419.2340.
Spirolactam 22c. The General Spirocyclization Procedure was followed at 80 ºC using amide substrate 21c
75 mg, 0.17 mmol). Upon consumption of the starting material, as determined by GC-MS, the reaction mixture
(
was concentrated onto Celite via rotary evaporation and chromatographed by automated flash column
chromatography on silica gel eluting with a gradient of 30-80% EtOAc/Hex to afford 22c (45 mg, 68%) as a
1
white amorphous solid. H NMR (CDCl , 300 MHz) δ 7.39-7.29 (m, 5H), 6.62 (d, J = 9.6 Hz, 1H), 6.42 (d, J =
3
9
.3 Hz, 1H), 6.34 (d, J = 9.9 Hz, 1H), 6.18 (apparent doublet due to overlapping peaks, 2H), 5.87 (d, J = 4.5 Hz,
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The Journal of Organic Chemistry
1
H), 5.02 (s, 1H), 3.78 (bs, 1H), 2.00-1.86 (m, 2H), 1.79 (s, 3H), 1.64-1.54 (m, 3H), 1.38-1.26 (m, 2H), 1.16-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
.01 (m, 3H); 13C{1H} NMR (CDCl , 75 MHz) δ 184.5, 171.1, 167.9, 156.5, 146.0, 135.1, 131.9, 131.5, 129.4,
3
-
1
129.1, 128.8, 125.5, 70.1, 61.9, 48.9, 32.7, 32.6, 25.5, 24.7, 24.6, 12.6; FT-IR (cm ) 3429, 3034, 2930, 2853,
+
1
665, 1561, 1342; HRMS (ES+) m/z calcd. for C H N O [M+H] 391.2022, found 391.2005.
2
4
27
2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
,4-Dimethyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (24a). The General Spirocyclization Procedure was
followed at 50 ºC using amide substrate 23a (38 mg, 0.2 mmol). Upon consumption of the starting material, as
determined by GC-MS, the reaction mixture was concentrated onto Celite via rotary evaporation and
chromatographed by automated flash column chromatography on silica gel eluting with a gradient of 30-80%
1
EtOAc/Hex to afford 24a (29 mg, 77%) as a white amorphous solid. H NMR (CDCl , 300 MHz) δ 6.56 (d, J =
3
10.2 Hz, 2 H), 6.39 (d, J = 10.2 Hz, 2 H), 6.14 (d, J = 1.5 Hz, 2H), 2.85 (s, 3H), 1.85 (d, J = 1.5 Hz, 3H);
-1
1
3C{1H} NMR (CDCl , 75 MHz) δ 184.1, 170.8, 155.2, 145.8, 133.2, 125.6, 69.0, 26.1, 12.6; FT-IR (cm )
3
+
3
358, 3065, 2940, 1669, 1388, 1361, 1060; HRMS (ES+) m/z calcd. for C H NO [M+H] 190.0868, found
11 12
2
190.0877.
7
-Chloro-4-methyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (24b). The General Spirocyclization
Procedure was followed at 50 ºC using amide substrate 23b (42 mg, 0.2 mmol). Upon consumption of the
starting material, as determined by GC-MS, the reaction mixture was concentrated onto Celite via rotary
evaporation and chromatographed by automated flash column chromatography on silica gel eluting with a
1
gradient of 30-80% EtOAc/Hex to afford 24b (32 mg, 76%) as a white amorphous solid. H NMR (CDCl , 300
3
MHz) δ 7.33 (s, 1H), 6.68 (s, 1H), 6.53 (d, J = 1.2 Hz, 1H), 6.10 (d, J = 1.2 Hz, 1H), 1.88 (s, 3H); 13C{1H}
-
1
NMR (CDCl , 75 MHz) δ 177.7, 173.3, 158.4, 146.4, 141.7, 135.1, 130.6, 125.7, 66.8, 12.7; FT-IR (cm ) 3291,
3
+
3
094, 3038, 1665, 1385, 1323, 1022; HRMS (ES+) m/z calcd. for C H ClNO [M+H] 210.0322, found
1
0
9
2
2
10.0325.
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